The immunopathogenesis associated with HIV-1 infection is characterized by several functional abnormalities of immune system cell populations and by a progressive decline in the numbers and functions of CD4+ T lymphocytes. In spite of many efforts, the mechanisms ultimately leading to the development of AIDS have not yet been fully elucidated. The general goal of this proposal is to characterize early HIV interactions as well as bystander effects of HIV-1 gene products on cell populations of the innate immunity system to the aim of defining novel mechanisms involved in viral persistence and immune system dysfunctions relevant to the comprehension of immunopathogenesis of AIDS. Based on the working hypothesis that the functional outcome of the immune response is likely to be determined by the type of innate immune response elicited, the project foresees the following objectives: i) Determine the effects of early HIV interaction with macrophages and DCs on the expression/activation of Toll-like receptors ii) Define the molecular signals triggered by early HIV/target cell interactions and their role in HIV mediated functional cell alterations iii) Characterize the immunomodulatory activities of HIV-1 Vpr accessory protein on effector cells linking innate and adaptive responses. It is expected that this research could provide the basis for a novel interpretation of important aspects of immunopathogenesis which may be critical to the ultimate development of effective prophylactic and therapeutic interventions.